Download PDF
Am J Perinatol 2023; 40(11): 1223-1231
DOI: 10.1055/s-0041-1735214
Original Article

Rectal Acetaminophen Improves Shunt Volume and Reduces Patent Ductus Arteriosus Ligation in Extremely Preterm Infants

Michael P. Castaldo
1   Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
,
Elaine Neary
1   Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
,
Adrianne R. Bischoff
1   Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
,
Maura H.F. Resende
1   Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
,
Dany E. Weisz
2   Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
3   Newborn and Developmental Pediatrics, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
,
Amish Jain
2   Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
4   Department of Pediatrics, Mount Sinai Hospital, Toronto, Ontario, Canada
,
Regan E. Giesinger 
1   Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
2   Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
,
Patrick J. McNamara
1   Newborn and Developmental Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
2   Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
› Author Affiliations
› Further Information
    Permissions and Reprints

Corrected by:

Corrigendum: Rectal Acetaminophen Improves Shunt Volume and Reduces Patent Ductus Arteriosus Ligation in Extremely Preterm InfantsAm J Perinatol 2023; 40(11): e1-e1
DOI: 10.1055/s-0044-1786510

Abstract

Objective An alternative therapy for preterm infants with a hemodynamically significant patent ductus arteriosus (hsPDA) is needed when cyclooxygenase inhibitors fail or where treatment is contraindicated due to coexisting renal failure, necrotizing enterocolitis, and/or intestinal perforation. No studies have evaluated the efficacy of per rectum (PR) acetaminophen. The study aimed to evaluate the efficacy of PR acetaminophen in modulating the risk of PDA ligation.

Study Design A retrospective matched case–control study was conducted to compare neonates born <29 weeks' gestation with evidence of hsDA, in an era when rescue rectal acetaminophen was used (January 2014–March 2018) as a treatment strategy, versus historical controls (July 2006–August 2012). All patients underwent comprehensive echocardiography assessment of ductal shunt volume according to a standardized protocol. Acetaminophen treated neonates were matched according to demographics, gestation, preintervention echocardiography features, and comorbidities. Control patients were selected when an echocardiography was performed at an equivalent postnatal age. Infants with a genetic syndrome, severe congenital malformation, or major forms of congenital heart disease excluding small atrial septal defect or ventricular septal defect, PDA, or patent formale ovale were excluded. The primary outcome was surgical ligation of the PDA. Secondary outcomes included echocardiography indices of hemodynamic significance, the composite of death, or severe BPD (defined by ventilator dependence at 36 weeks postmenstrual age). Descriptive statistics and univariate (t-tests, Fisher's exact test, and Mann–Whitney U test) analyses were used to evaluate clinical and echocardiography characteristics of the groups and compare outcomes.

Results Forty infants (20 cases and 20 controls), with similar demographic and echocardiography features, were compared. Cases received 6.8 ± 0.7 days (60 mg/kg/day) of PR acetaminophen. Responders (n = 12, 60%) had echocardiography evidence of reduced ductal diameter (2.2 mm [1.9–2.6] to 1.1 mm [0–1.7], p = 0.002), left ventricular output (363 ± 108–249 ± 61 mL/min/kg; p = 0.002) and left atrium to aortic root ratio (1.7 ± 0.3–1.3 ± 0.2; p = 0.002) following treatment. The rate of PDA ligation was 50% lower (p = 0.02) and composite outcome of death or severe bronchopulmonary dysplasia was reduced (p = 0.04) in the acetaminophen group.

Conclusion Rectal acetaminophen was associated with improvement in echocardiography indices of PDA shunt volume, a 50% reduction in PDA ligation rates and a reduction in the composite outcome of death or severe BPD. Pharmacologic and further prospective clinical studies are needed.

Key Points

  • Many preterm infants encounter the clinical consequences of a hemodynamically significant PDA.

  • The merits and optimal timing of PDA ligation remains an area of controversy amongst neonatologists.

  • Cyclooxygenase inhibitors are associated with adverse events or are often contraindicated.

Keywords

patent ductus arteriosus - surgical ligation - acetaminophen - bronchopulmonary dysplasia - mortality

Note

There are no prior publications or submissions with any overlapping information, including studies and patients. The manuscript has not been and will not be submitted to any other journal while it is under consideration by the American Journal of Perinatology.


Authors' Contributions

M.P.C. wrote the first draft of the manuscript, with no honorarium, grant, or other form of payment received to produce the manuscript. P.J.M. was responsible for hypothesis generation, study design analysis, and final approval of the manuscript. All listed authors have seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript.


Supplementary Material



Publication History

Received: 08 September 2020

Accepted: 12 July 2021

Article published online:
28 September 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Hamrick SE, Hansmann G. Patent ductus arteriosus of the preterm infant. Pediatrics 2010; 125 (05) 1020-1030
    Google Scholar
  • 2 Sellmer A, Bjerre JV, Schmidt MR. et al. Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Arch Dis Child Fetal Neonatal Ed 2013; 98 (06) F505-F510
    Google Scholar
  • 3 Erdeve O, Yurttutan S, Altug N. et al. Oral versus intravenous ibuprofen for patent ductus arteriosus closure: a randomised controlled trial in extremely low birthweight infants. Arch Dis Child Fetal Neonatal Ed 2012; 97 (04) F279-F283
    Google Scholar
  • 4 Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr 2011; 158 (04) 549-554.e1
    Google Scholar
  • 5 Van Overmeire B, Smets K, Lecoutere D. et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000; 343 (10) 674-681
    Google Scholar
  • 6 Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev 2015; (02) CD003481
    Google Scholar
  • 7 Bagnoli F, Rossetti A, Messina G, Mori A, Casucci M, Tomasini B. Treatment of patent ductus arteriosus (PDA) using ibuprofen: renal side-effects in VLBW and ELBW newborns. J Matern Fetal Neonatal Med 2013; 26: 423-429
    Google Scholar
  • 8 Erdeve O, Sarici SU, Sari E, Gok F. Oral-ibuprofen-induced acute renal failure in a preterm infant. Pediatr Nephrol 2008; 23 (09) 1565-1567
    Google Scholar
  • 9 Fujii AM, Brown E, Mirochnick M, O'Brien S, Kaufman G. Neonatal necrotizing enterocolitis with intestinal perforation in extremely premature infants receiving early indomethacin treatment for patent ductus arteriosus. J Perinatol 2002; 22: 535-540
    Google Scholar
  • 10 Shorter NA, Liu JY, Mooney DP, Harmon BJ. Indomethacin-associated bowel perforations: a study of possible risk factors. J Pediatr Surg 1999; 34 (03) 442-444
    Google Scholar
  • 11 Akima S, Kent A, Reynolds GJ, Gallagher M, Falk MC. Indomethacin and renal impairment in neonates. Pediatr Nephrol 2004; 19 (05) 490-493
    Google Scholar
  • 12 Clyman RI. Mechanisms regulating the ductus arteriosus. Biol Neonate 2006; 89 (04) 330-335
    Google Scholar
  • 13 Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 2013; 21 (03) 201-232
    Google Scholar
  • 14 Dang D, Wang D, Zhang C, Zhou W, Zhou Q, Wu H. Comparison of oral paracetamol versus ibuprofen in premature infants with patent ductus arteriosus: a randomized controlled trial. PLoS One 2013; 8 (11) e77888
    Google Scholar
  • 15 Oncel MY, Yurttutan S, Erdeve O. et al. Oral paracetamol versus oral ibuprofen in the management of patent ductus arteriosus in preterm infants: a randomized controlled trial. J Pediatr 2014; 164 (03) 510-4.e1
    Google Scholar
  • 16 Fajardo MF, Claure N, Swaminathan S. et al. Effect of positive end-expiratory pressure on ductal shunting and systemic blood flow in preterm infants with patent ductus arteriosus. Neonatology 2014; 105 (01) 9-13
    Google Scholar
  • 17 Resende MH, More K, Nicholls D, Ting J, Jain A, McNamara PJ. The impact of a dedicated patent ductus arteriosus ligation team on neonatal health-care outcomes. J Perinatol 2016; 36 (06) 463-468
    Google Scholar
  • 18 Clyman R, Cassady G, Kirklin JK, Collins M, Philips III JB. The role of patent ductus arteriosus ligation in bronchopulmonary dysplasia: reexamining a randomized controlled trial. J Pediatr 2009; 154 (06) 873-876
    Google Scholar
  • 19 Noori S, McCoy M, Friedlich P. et al. Failure of ductus arteriosus closure is associated with increased mortality in preterm infants. Pediatrics 2009; 123 (01) e138-e144
    Google Scholar
  • 20 Schena F, Francescato G, Cappelleri A. et al. Association between hemodynamically significant patent ductus arteriosus and bronchopulmonary dysplasia. J Pediatr 2015; 166 (06) 1488-1492
    Google Scholar
  • 21 Wickremasinghe AC, Rogers EE, Piecuch RE. et al. Neurodevelopmental outcomes following two different treatment approaches (early ligation and selective ligation) for patent ductus arteriosus. J Pediatr 2012; 161 (06) 1065-1072
    Google Scholar
  • 22 Bose CL, Laughon MM. Patent ductus arteriosus: lack of evidence for common treatments. Arch Dis Child Fetal Neonatal Ed 2007; 92 (06) F498-F502
    Google Scholar
  • 23 Weisz DE, More K, McNamara PJ, Shah PS. PDA ligation and health outcomes: a meta-analysis. Pediatrics 2014; 133 (04) e1024-e1046
    Google Scholar
  • 24 Weisz DE, Mirea L, Rosenberg E. et al. Association of patent ductus arteriosus ligation with death or neurodevelopmental impairment among extremely preterm infants. JAMA Pediatr 2017; 171 (05) 443-449
    Google Scholar
  • 25 El-Khuffash AF, Jain A, McNamara PJ. Ligation of the patent ductus arteriosus in preterm infants: understanding the physiology. J Pediatr 2013; 162 (06) 1100-1106
    Google Scholar
  • 26 Ulrich TJB, Hansen TP, Reid KJ, Bingler MA, Olsen SL. Post-ligation cardiac syndrome is associated with increased morbidity in preterm infants. J Perinatol 2018; 38 (05) 537-542
    Google Scholar
  • 27 Teixeira LS, Shivananda SP, Stephens D, Van Arsdell G, McNamara PJ. Postoperative cardiorespiratory instability following ligation of the preterm ductus arteriosus is related to early need for intervention. J Perinatol 2008; 28 (12) 803-810
    Google Scholar
  • 28 Weisz DE, Martins FF, Nield LE, El-Khuffash A, Jain A, McNamara PJ. Acetaminophen to avoid surgical ligation in extremely low gestational age neonates with persistent hemodynamically significant patent ductus arteriosus. J Perinatol 2016; 36 (08) 649-653
    Google Scholar
  • 29 Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Ductal closure with paracetamol: a surprising new approach to patent ductus arteriosus treatment. Pediatrics 2011; 128 (06) e1618-e1621
    Google Scholar
  • 30 Oncel MY, Yurttutan S, Uras N. et al. An alternative drug (paracetamol) in the management of patent ductus arteriosus in ibuprofen-resistant or contraindicated preterm infants. Arch Dis Child Fetal Neonatal Ed 2013; 98 (01) F94
    Google Scholar
  • 31 Jasani B, Kabra N, Nanavati RN. Oral paracetamol in treatment of closure of patent ductus arteriosus in preterm neonates. J Postgrad Med 2013; 59 (04) 312-314
    Google Scholar
  • 32 A EL-K, James AT, Cleary A, Semberova J, Franklin O, Miletin J. Late medical therapy of patent ductus arteriosus using intravenous paracetamol. Arch Dis Child Fetal Neonatal Ed 2015; 100: F253-F256
    Google Scholar
  • 33 Jibril F, Sharaby S, Mohamed A, Wilby KJ. Intravenous versus oral acetaminophen for pain: systematic review of current evidence to support clinical decision-making. Can J Hosp Pharm 2015; 68 (03) 238-247
    Google Scholar
  • 34 van Lingen RA, Deinum JT, Quak JM. et al. Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates. Arch Dis Child Fetal Neonatal Ed 1999; 80 (01) F59-F63
    Google Scholar
  • 35 Levy G, Khanna NN, Soda DM, Tsuzuki O, Stern L. Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion. Pediatrics 1975; 55 (06) 818-825
    Google Scholar
  • 36 Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kinetics in neonates, children, and adults. Clin Pharmacol Ther 1976; 19 (03) 284-294
    Google Scholar
  • 37 Lederman S, Fysh WJ, Tredger M, Gamsu HR. Neonatal paracetamol poisoning: treatment by exchange transfusion. Arch Dis Child 1983; 58 (08) 631-633
    Google Scholar
  • 38 Terrin G, Conte F, Oncel MY. et al. Paracetamol for the treatment of patent ductus arteriosus in preterm neonates: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2016; 101 (02) F127-F136
    Google Scholar
  • 39 Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Age-related differences and therapeutic implications. Clin Pharmacokinet 1980; 5 (06) 485-527
    Google Scholar